Skip to main content
SpringerLink
Log in

Preparation of a Sustained-Release Nebulized Aerosol of R-terbutaline Hydrochloride Liposome and Evaluation of Its Anti-asthmatic Effects via Pulmonary Delivery in Guinea Pigs

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

An aerosolized liposome formulation for the pulmonary delivery of an anti-asthmatic medication was developed. Asthma treatment usually requires frequent administration of medication for a sustained bronchodilator response. Liposomes are known for their sustained drug release capability and thus would be a suitable delivery system for prolonging the therapeutic effect of anti-asthmatic medication. Liposomes prepared by thin film hydration were loaded with a model drug, R-terbutaline hydrochloride(R-TBH), using an ammonium sulfate-induced transmembrane electrochemical gradient. This technique provided an encapsulation efficiency of up to 71.35% and yielded R-TBH liposomes with a particle size of approximately 145 ± 20 nm. According to stability studies, these R-TBH liposomes should be stored at 4°C before usage. Compared to R-TBH solution, which showed 90.84% release within 8 h, liposomal R-TBH had a cumulative release of 73.53% at 37°C over 192 h. A next generation impactor (NGI) was used to analyze the particle size distribution in the lungs of R-TBH liposome aerosol in vitro at 5°C. The therapeutic efficacy of the nebulized aerosol of the R-TBH liposomes was assessed via pulmonary delivery in guinea pigs. The results showed that, compared to the R-TBH solution group, the R-TBH liposome group had a prolonged anti-asthma effect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Emami J, Varshosaz J, Jafari E. Comparison of hydrophilic natural gums and cellulosic polymers in formulation of sustained-release matrix tablets of terbutaline sulfate. Res Pharm Sci. 2012;1(1):30–9.

    Google Scholar 

  2. Hartley D, Middlemiss D. Absolute configuration of the optical isomers of salbutamol. J med Chem. 1971;14(9):895–6.

    Article  CAS  Google Scholar 

  3. Wetterlin K. Resolution of terbutaline, a new. beta.-sympathomimetic amine. J med Chem. 1972;15(11):1182–3.

    Article  CAS  PubMed  Google Scholar 

  4. Borgstrom L, Nyberg L, Jonsson S, et al. Pharmacokinetic evaluation in man of terbutaline given as separate enantiomers and as the racemate. Br J Clin Pharmacol. 1989;27(1):49–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Guan S, Hu C, He M, et al. Comparative pharmacokinetics and bile transformation of R-enantiomer and racemic bambuterol after single-dose intravenous, oral administration in rats and beagle dogs. Eur J Drug Metab Pharmacokinet. 2015;40(4):453–60.

    Article  CAS  PubMed  Google Scholar 

  6. Zhou T, Zhao T, Cheng Q, et al. A sensitive LC-MS/MS method for simultaneous determination of R-bambuterol and its active metabolite R-terbutaline in human plasma and urine with application to a clinical pharmacokinetic study. Biomed Chromatogr. 2014;28(7):994–1002.

    Article  CAS  PubMed  Google Scholar 

  7. Jeppsson AB, Johansson U, Waldeck B. Steric aspects of agonism and antagonism at β-adrenoceptors: experiments with the enantiomers of terbutaline and pindolol. Basic Clin Pharmacol Toxicol. 1984;54(4):285–91.

    CAS  Google Scholar 

  8. Aagaard L, Hansen EH. Paediatric adverse drug reactions following use of asthma medications in Europe from 2007 to 2011. Int J Clin Pharm. 2014;36(6):1222–9.

    Article  CAS  PubMed  Google Scholar 

  9. Borgström L, Nilsson M. A method for determination of the absolute pulmonary bioavailability of inhaled drugs: terbutaline. Pharm res. 1990;7(10):1068–70.

    Article  PubMed  Google Scholar 

  10. Stewart IC, Rhind GB, Power JT, et al. Effect of sustained release terbutaline on symptoms and sleep quality in patients with nocturnal asthma. Thorax. 1987;42(10):797–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dahl R, Pedersen B, Hägglöf B. Nocturnal asthma: effect of treatment with oral sustained-release terbutaline, inhaled budesonide, and the two in combination. J Allergy Clin Immunol Pract. 1989;83(4):811–5.

    Article  CAS  Google Scholar 

  12. Westermann CJJ, Van Weelden BM, Laros CD. Sustained-release terbutaline in nocturnal asthma. Allergy. 1986;41(4):308–10.

    Article  CAS  PubMed  Google Scholar 

  13. Dahl R, Harving H, Säwedal L, et al. Terbutaline sustained-release tablets in nocturnal asthma—a placebo-controlled comparison between a high and a low evening dose. Br J dis Chest. 1988;82:237–41.

    Article  CAS  PubMed  Google Scholar 

  14. Holimon TD, Chafin CC, Self TH. Nocturnal asthma uncontrolled by inhaled corticosteroids. Drugs. 2001;61(3):391–418.

    Article  CAS  PubMed  Google Scholar 

  15. Loira-Pastoriza C, Todoroff J, Vanbever R. Delivery strategies for sustained drug release in the lungs. J Appl Physiol. 2014;75:81–91.

    CAS  Google Scholar 

  16. Lasic DD. Recent developments in medical applications of liposomes: sterically stabilized liposomes in cancer therapy and gene delivery in vivo. J Control Release. 1997;48(2):203–22.

    Article  CAS  Google Scholar 

  17. El-Sherbiny IM, El-Baz NM, Yacoub MH. Inhaled nano- and microparticles for drug delivery. Glob Cardiol Sci Pract. 2015:2.

  18. Schreier H, Gonzalez-Rothi RJ, Stecenko AA. Pulmonary delivery of liposomes. J Control Release. 1993;24(1):209–23.

    Article  CAS  Google Scholar 

  19. Zhang X, Liu Q, Hu J, et al. An aerosol formulation of R-salbutamol sulfate for pulmonary inhalation. Acta Pharm sin B. 2014;4(1):79–85.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yang Z, Lu A, Chi Kwan Wong B, et al. Effect of liposomes on the absorption of water-soluble active pharmaceutical ingredients via oral administration. Curr Pharm des. 2013;19(37):6647–54.

    Article  CAS  PubMed  Google Scholar 

  21. Vargas MH, Sommer B, Bazán-Perkins B, et al. Airway responsiveness measured by barometric plethysmography in guinea pigs. Vet res Commun. 2010;34(7):589–96.

    Article  PubMed  Google Scholar 

  22. Begin R, Renzetti AD, Bigler AH, et al. Flow and age dependence of airway closure and dynamic compliance. J Appl Physiol. 1975;38(2):199–207.

    Article  CAS  PubMed  Google Scholar 

  23. Saini D, Biris AS, Srirama PK, et al. Particle size and charge distribution analysis of pharmaceutical aerosols generated by inhalers. Pharm dev Technol. 2007;12(1):35–41.

    Article  CAS  PubMed  Google Scholar 

  24. Martin RJ. Therapeutic significance of distal airway inflammation in asthma. J Allergy Clin Immunol. 2002;109(2):S447–60.

    Article  PubMed  Google Scholar 

  25. Carvalho TC, Peters JI, Williams RO. Influence of particle size on regional lung deposition–what evidence is there? Int J Pharm. 2011;406(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  26. Yang W, Peters JI, Williams RO. Inhaled nanoparticles—a current review. Int J Pharm. 2008;356(1):239–47.

    Article  CAS  PubMed  Google Scholar 

  27. Murthy SN, Hiremath SRR. Physical and chemical permeation enhancers in transdermal delivery of terbutaline sulphate. AAPS PharmSciTech. 2001;2(1):1–5.

    Article  PubMed Central  Google Scholar 

  28. Gillies HC, Rogers HJ, Spector RG, Trounce JR. A textbook of clinical pharmacology. 2nd ed. London: Edward Arnold; 1986. p. 473.

    Google Scholar 

  29. Sahin S, Selek H, Ponchel G, et al. Preparation, characterization and in vivo distribution of terbutaline sulfate loaded albumin microspheres. J Control Release. 2002;82(2):345–58.

    Article  CAS  PubMed  Google Scholar 

  30. Hashem FM, Nasr M, Fathy G, et al. Formulation and in vitro and in vivo evaluation of lipid-based terbutaline sulphate bi-layer tablets for once-daily administration. AAPS PharmSciTech. 2016;17(3):727–34.

    Article  CAS  PubMed  Google Scholar 

  31. Khattab I, Bandarkar F, Lila A. Formulation and optimization of sustained release terbutalinesulfate microspheres using response surface methodology. Drug Discov Ther. 2009;3:123–35.

    CAS  PubMed  Google Scholar 

  32. Al-Akayleh F, Al Remawi M, Rashid I, et al. Formulation and in vitro assessment of sustained release terbutalinesulfate tablet made from binary hydrophilic polymer mixtures. Pharm dev Technol. 2013;18(5):1204–12.

    Article  CAS  PubMed  Google Scholar 

  33. Hadi MA, Rao AS, Abhinetri V, et al. Design and in-vitro evaluation of multiparticulate drug delivery system of terbutaline sulphate for the treatment of nocturnal asthma. Pharm Lett. 2012;4(6):1777–85.

    Google Scholar 

  34. Dyreborg A, Krogh N, Backer V, et al. Pharmacokinetics of oral and inhaled terbutaline after exercise in trained men. Front Pharmacol. 2016;7:150.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Palakurthi S, Govardhanachary M, Vyas SP, et al. Biodistribution of liposomes of terbutaline sulfate in guinea pigs. Drug dev Ind Pharm. 2000;26(10):1099–105.

    Article  CAS  PubMed  Google Scholar 

  36. Joshi MR, Misra AN. Liposomes of terbutaline sulphate: in vitro and in vivo studies. Indian J Exp Biol. 1999;37(9):881–7.

    CAS  PubMed  Google Scholar 

  37. Fielding RM, Abra RM. Factors affecting the release rate of terbutaline from liposome formulations after intratracheal instillation in the guinea pig. Pharm res. 1992;9(2):220–3.

    Article  CAS  PubMed  Google Scholar 

  38. Brown RA, Schanker LS. Absorption of aerosolized drugs from the rat lung. Drug Metab Dispos. 1983;11(4):355–60.

    CAS  PubMed  Google Scholar 

  39. Brain JD, Knudson DE, Sorokin SP, et al. Pulmonary distribution of particles given by intratracheal instillation or by aerosol inhalation. Environ res. 1976;11(1):13–33.

    Article  CAS  PubMed  Google Scholar 

  40. Patlolla RR, Chougule M, Patel AR, et al. Formulation, characterization and pulmonary deposition of nebulized celecoxib encapsulated nanostructured lipid carriers. J Control Release. 2010;144(2):233–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schilt Y, Berman T, Wei X, et al. Using solution X-ray scattering to determine the high-resolution structure and morphology of PEGylated liposomal doxorubicin nanodrugs. Biochim Biophys Acta. 2016;1860(1):108–19.

    Article  CAS  PubMed  Google Scholar 

  42. Gupta V, Gupta N, Shaik IH, et al. Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension. J Control Release. 2013;167(2):189–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Haran G, Cohen R, Bar LK, et al. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta. 1993;1151(2):201–15.

    Article  CAS  PubMed  Google Scholar 

  44. Lindner LH, Hossann M. Factors affecting drug release from liposomes. Curr Opin Drug Discov Devel. 2010;13(1):111–23.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Key-Pharma Biomedical Inc. for providing R-terbutaline hydrochloride. This work was supported by the Ministry of Science and Technology of China under Grant 201305017 and the Ministry of Science and Technology of Guangdong Province, China under Grant 2015B010109004.

Author information

Authors and Affiliations

  1. School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China

    Qingrui Li, Shuyao Zhan, Qing Liu, Hao Su, Xi Dai, Hai Wang & Huimin Beng

  2. Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China

    Wen Tan

Authors
  1. Qingrui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuyao Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hao Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xi Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Huimin Beng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wen Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wen Tan.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

ESM 1

(DOCX 123 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Q., Zhan, S., Liu, Q. et al. Preparation of a Sustained-Release Nebulized Aerosol of R-terbutaline Hydrochloride Liposome and Evaluation of Its Anti-asthmatic Effects via Pulmonary Delivery in Guinea Pigs. AAPS PharmSciTech 19, 232–241 (2018). https://doi.org/10.1208/s12249-017-0816-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-017-0816-z

KEY WORDS

Search

Navigation